Vesicle Synaptotagmin

Littleton, JT and Bellen, HJ (1995) Synaptotagmin controls and modulates synaptic-vesicle fusion in a Ca + dependent manner. Trends Neurosci. 18 177-183. 

Amphiphysin Nerve-terminal protein that associates with synaptic vesicles probably via AP2 bound to synaptotagmin. May function in endocytosis. 

Synaptotagmins are yet another family of Ca2+-binding proteins, localized on the membranes of synaptic vesicles, where they seem to be involved in the release of neurotransmitters. While the mechanism by which they are involved in Ca2+-mediated synaptic transmission is unclear, it seems likely that the neurotoxicity of heavy metals such as Pb is due to a higher affinity of synaptotagmins for Pb2+ than for Ca2+. 

The decisive element in exocytosis is the interaction between proteins known as SNAREs that are located on the vesicular membrane (v-SNAREs) and on the plasma membrane (t-SNAREs). In the resting state (1), the v-SNARE synaptobrevin is blocked by the vesicular protein synaptotagmin. When an action potential reaches the presynaptic membrane, voltage-gated Ca "" channels open (see p. 348). Ca "" flows in and triggers the machinery by conformational changes in proteins. Contact takes place between synaptobrevin and the t-SNARE synaptotaxin (2). Additional proteins known as SNAPs bind to the SNARE complex and allow fusion between the vesicle and the plasma membrane (3). The process is supported by the hydrolysis of GTP by the auxiliary protein Rab. 

In addition to functioning as Ca2+-sensors for vesicle exocytosis, synaptotag-mins may be involved in vesicle endocytosis, particularly the decision between kiss-and-run versus full exocytosis. Such a role would be economical in linking fusion-pore opening (which is triggered by Ca2+-binding to synaptotagmin) to fusion-pore expansion or contraction, but the precise mechanisms involved have not yet been explored. 

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The experiments using these optical tools consistently supported the premise that synaptic vesicle exocytosis and endocytosis are tightly coupled processes. This largely kinetic coupling is also backed up by recent molecular evidence that proteins critical for exocytosis such as synaptotagmin and synaptobrevin, are also essential for triggering endocytosis (Poskanzer et al., 2003 Deak et al., 2004 Nicholson-Tomishima and Ryan, 2004). 

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Schivell AE, Batchelor RH, Bajjalieh SM (1996) Isoform-specific, calcium-regulated interaction of the synaptic vesicle proteins SV2 and synaptotagmin. J Biol Chem 271 27770-27775. 

Fig. 4 Stages in synaptic vesicle exocytosis. Putative intermediate steps on the molecular pathway to synaptic vesicle fusion. Vesicle delivery and tethering to the presynaptic membrane most likely involves Rab-proteins and their effectors. So far, the nature of a speculative docking complex (dc) is unclear, but docking appears to be independent from SNARE proteins. In the primed state, SNAREs have assembled into a complex probably stabilized by complexin (Cpx). The fusion reaction is arrested until the intracellular calcium concentration increases. The putative calcium sensor for fast neurotransmitter release, synaptotagmin 1 (Syt), binds to intracellular calcium and in turn triggers fusion by associating with the presynaptic membrane and interacting with the SNARE complex, thereby displacing complexin (Tang et al. 2006).

Cousin MA, Robinson PJ (2001) The dephosphins dephosphorylation by calcineurin triggers synaptic vesicle endocytosis. Trends Neurosci 24 659-65 Craxton M (2004) Synaptotagmin gene content of the sequenced genomes. BMC Genomics 5 43 Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443 651-7... 

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